Highlights from Recent Cancer Literature
Journal: Cancer Research (2011)

Nieman KM, Kenny HA, Penicka CV, Ladanyi A, Buell-Gutbrod R, Zillhardt M, et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nature Med 2011;17:1498–503.Clinical observations indicate that the most common site of ovarian cancer metastasis is the abdominal omentum, a fatty organ that extends from the stomach to cover the intestines and is primarily composed of adipocytes. Metastasis is highly dependent on the surrounding microenvironment, but little is known regarding the preferential spread of ovarian cancer cells to the omentum. Nieman and colleagues have now established an important interaction between human ovarian cancer cells and adipocytes that they have recapitulated with a murine model implicating adipocytes and altered metabolic programming as a regulator of omental spread of ovarian cancer. The authors found that human ovarian cancer cells localized to the omentum of immune-deficient nu/nu mice within 20 minutes after intraperitoneal injection. Inhibition of adipokines, including interleukin (IL)-8, reduced homing of the ovarian cancer cells to omental adipocytes in vivo. Whereas several types of carcinoma cells, including ovarian, breast, and colon, accumulate lipids when cultured with primary human omental adipocytes (as shown in green in the accompanying image, where nuclei of primary human adipocytes are shown in purple), Nieman and colleagues revealed that lipids were in fact transferred from adipocytes to ovarian cancer cells. The authors suggest that an increase in lipolytic breakdown of triglycerides in adipocytes and oxidation of fatty acids in ovarian cancer cells promote ovarian cancer cell proliferation. Finally, the authors identified fatty acid binding protein 4 (FABP4) as a potential mediator of ovarian cancer metastasis based on their results showing that orthotopic or intraperitoneal injection of mouse ovarian cancer cells into FABP4-deficient mice resulted in a dramatic reduction of metastasis. The model described by the authors suggests a role for both adipocytes and altered lipid metabolism in promoting intra-abdominal metastasis and identifies FABP4 as a potential therapeutic target.Shakya R, Reid LJ, Reczek CR, Cole F, Egli D, Lin CS, et al. BRCA1 tumor suppression depends on BRCT phosphoprotein binding, but not its E3 ligase activity. Science 2011;334:525–8.BRCA1 is an inherited breast and ovarian cancer susceptibility gene. The carboxy-terminus of BRCA1 binds phosphoproteins, whereas the amino terminus contains E3 ubiquitin ligase activity. Mutations in either domain are associated with increased cancer susceptibility, suggesting that both are important for tumor suppression by BRCA1. Shakya and colleagues examined genetically engineered mice with preserved phosphoprotein binding and defective E3 ligase activity, as well as the reciprocal mice preserving E3 ligase and deficient in phosphoprotein recognition. They next incorporated these mutants into 2 genetically engineered models for breast cancer (one driven by Brca1 deficiency alone, and a second driven by combined deficiency of Brca1 and p53), and into a genetically engineered pancreatic model (driven by activated Kras in the context of Brca1 deficiency). In all 3 models, phosphoprotein binding functions of Brca1 were critical for tumor suppression, whereas E3 ligase activity was dispensable. Thus, the phosphoprotein binding domain of Brca1, which mediates DNA repair activities, is required for tumor suppression, whereas the conserved E3 ligase activity, which effects ubiquitination of multiple substrate proteins, likely serves a cancer-independent function.Yang W, Xia Y, Ji H, Zheng Y, Liang J, Huang W, et al. Nuclear PKM2 regulates beta-catenin transactivation upon EGFR activation. Nature. 2011 Nov 6. [Epub ahead of print].The embryonic form of pyruvate kinase, PKM2, is frequently reexpressed in cancer. PKM2 promotes tumor growth by shunting metabolism toward production of glycolytic intermediates critical to macromolecular biosynthesis, at the expense of driving formation of ATP. Does PKM2 play additional roles in cancer that are independent of metabolism? To address this question, Yang and colleagues examined human glioma cells and analyzed the differential response of PKM1 and PKM2 to activation of epidermal growth factor receptor (EGFR). They found that PKM2, but not PKM1, translocated to the nucleus in response to activation of EGFR, where it bound phosphorylated β-catenin. The complex of PKM2 and β-catenin in turn activated the cyclin D1 promoter and was critical both to EGF-induced proliferation and development of brain tumors in xenograft models. To investigate the relevance of these results to the development of human brain tumors, the authors examined primary human glioblastoma tumors, demonstrating a correlation between phosphorylated β-catenin and accumulation of PKM2 into the nucleus of cancer cells, with increased levels of both proteins correlating negatively with prognosis. These results suggest that PKM2 has a nonmetabolic function in development of brain tumors, cooperating with β-catenin in an EGFR-dependent and Wnt-independent manner, to drive gliomagenesis.Horikawa M, Minard-Colin V, Matsushita T, Tedder TF. Regulatory B cell production of IL-10 inhibits lymphoma depletion during CD20 immunotherapy in mice. J Clin Invest 2011;121:4268–80.Most people think that the main function of B cells is in antibody production, but B cells can also have other important regulatory actions in the immune system. A subset of B-regulatory cells, called B10 cells, limit T-cell–dependent inflammation and autoimmunity through their production of the potent immunosuppressive cytokine interleukin (IL)-10. As reported recently, IL-10–producing B cells may also contribute to development of the immunosuppressive microenvironment typically present in solid (and liquid) tumors. A new study reported by Horikawa and colleagues has implicated B10 cells in treatment failure of some patients with non-Hodgkin lymphoma (NHL). Because more than 90% of all NHLs exhibit a B-cell phenotype and express the cell-surface antigen CD20, an anti-CD20 therapeutic antibody, rituximab, has become a standard treatment for this disease. However, less than 50% of patients exhibit a durable response following therapy, and the reasons underlying treatment failure have not been understood. Horikawa and colleagues hypothesized that endogenous B cells could influence the response of the malignant B cells to anti-CD20 antibodies. Using a transplantable CD20-positive mouse model of lymphoma in wild-type and CD20−/− mice, they first revealed that a murine anti-CD20 monoclonal antibody resulted in antitumor activity in the wild-type but not the CD20−/− mice. This result suggested that endogenous B cells were involved in treatment resistance in the CD20−/−mice (which exhibit otherwise “normal” B-cell development) because normal B cells could not be depleted by the therapeutic antibody. After anti-CD20 treatment, B10 cells were still present in CD20−/−mice. Furthermore, adoptive transfer of CD20−/− B cells enriched for B10 populations to wild-type mice eliminated the therapeutic activity of the anti-CD20 antibody. However, if the transferred B cells were not only CD20−/−, but also IL-10−/−, the antibody treatment was successful. The depletion of both NHL and normal B cells by the anti-CD20 antibody required functional macrophages; B10 cells inhibited antibody-mediated monocyte activation and effector function. The authors went on to reveal that they could overcome the negative effects of B10 cells in wild-type mice by activation of innate immune cells with a Toll-like receptor 3 agonist, namely poly (I:C). Combining poly (I:C) with the anti-CD20 antibody significantly enhanced depletion of lymphoma cells in both wild-type and CD20−/− mice. An obvious translational implication of this work is addition of poly (I:C) to rituximab regimens in NHL patients. However, this combination may not be possible, as the former is quite toxic to humans, but other similar agents can be used safely.Note: Breaking Advances are written by Cancer Research Editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.